WO2000053180A1 - Composes de 6-azaindole antagonistes de la gonadoliberine - Google Patents

Composes de 6-azaindole antagonistes de la gonadoliberine Download PDF

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WO2000053180A1
WO2000053180A1 PCT/US2000/005727 US0005727W WO0053180A1 WO 2000053180 A1 WO2000053180 A1 WO 2000053180A1 US 0005727 W US0005727 W US 0005727W WO 0053180 A1 WO0053180 A1 WO 0053180A1
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substituted
alkyl
aryl
compound
aralkyl
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PCT/US2000/005727
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Thomas F. Walsh
Feroze Ujjainwalla
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Merck & Co., Inc.
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Priority to EP00912179A priority Critical patent/EP1165075A4/fr
Priority to JP2000603669A priority patent/JP2002538205A/ja
Priority to AU33950/00A priority patent/AU3395000A/en
Priority to CA002367121A priority patent/CA2367121A1/fr
Publication of WO2000053180A1 publication Critical patent/WO2000053180A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • the gonadotropin-releasing hormone also referred to as luteinizing hormone-releasing hormone (LHRH)
  • LHRH luteinizing hormone-releasing hormone
  • LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
  • GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH/FSH release.
  • GnRH -based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid- dependent neoplasia, most notably cancers of the prostate, breast and ovary.
  • GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women.
  • the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • bisphosphonates bisphosphonic acids
  • other agents such as growth hormone secretagogues
  • a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a- cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a- androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-trifluoro- methylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • a compound of the present invention may be used as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
  • peptide GnRH antagonists such as Antide and azaline B
  • Non-peptide GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten. Non-peptide GnRH antagonists offer the possible advantage of oral adminstration. Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
  • WO 90/05721 discloses alpha-amino-indole-3-acetic acids useful as anti- diabetic, anti-obesity and anti-atherosclerotic agents.
  • French patent 2,181,559 discloses indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity.
  • Belgian patent 879381 discloses 3-aminoalkyl-lH-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.
  • U.S. Patent Nos. 5,756,507, 5,780,437 and 5,849,764 also disclose substituted arylindoles as non-peptide antagonists of GnRH.
  • the present invention relates to compounds which are non-peptide antagonists of GnRH which can be used to treat a variety of sex-hormone related conditions in men and women, to methods for their preparation, and to methods and pharmaceutical compositions containing said compounds for use in mammals.
  • the compounds of the present invention are useful to treat a variety of sex-hormone related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasias such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertophy.
  • the compounds of the invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.
  • the compounds of the invention may be useful in in vitro fertilization and as contraceptives.
  • the compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids and in contraception. They may also be useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive.
  • the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril
  • an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor
  • the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza-5a- cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a- androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-trifluoro- methylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • a compound of the present invention may be used as described in U.S. Patent No. 5,824,286 which discloses the administration of peptide GnRH antagonists such as Antide and azaline B to premenopausal women to enhance the readability of mammographic film relative to a mammogram effected in the absence of the administration.
  • peptide GnRH antagonists such as Antide and azaline B
  • the present invention relates to compounds of the general formula
  • A is Ci-C ⁇ alkyl, substituted Ci-C ⁇ alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, C3-C6 alkenyl, substituted C3-C6 alkenyl, C3-C6 alkynyl, substituted C3-C6 alkynyl, Ci-C ⁇ alkoxy, or C0-C5 alkyl-S(0) n -Co-C5 alkyl, C0-C5 alkyl- O-C0-C5 alkyl, C0-C5 alkyl-NRi8-Co-C5 alkyl where R ⁇ .
  • R ⁇ is hydrogen, Ci-C ⁇ alkyl, substituted CI-CQ alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and R5.
  • Y is B, C or a bond;
  • B is O, S(0) n , C(O), NR ⁇ 8 or C(RnR ⁇ 2 )p
  • C is B(CH 2 ) P -;
  • R2 is hydrogen, C1-C6 alkyl, substituted C ⁇ -C6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl -ORn ;
  • R3, R4 and R5 are independently hydrogen, Ci-C ⁇ alkyl, substituted
  • R ⁇ is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, C1-C3 perfluoroalkyl, CN, NO2, halogen,
  • R7 is hydrogen, C1-C6 alkyl, or substituted C ⁇ -C6 alkyl, unless X is hydrogen or halogen, then R7 is absent;
  • R 8 is C(O)OR 2 0, C(0)NR2 ⁇ R21, NR20R2 C(O)R 2 0,
  • NR 2 lC(O)R 2 0, NR2lC(O)NR20R2 NR 2 ⁇ S(0) 2 R2L NR2lS(O) 2 NR20R21, OC(O)R 2 0, OC(0)NR 2 ⁇ R21, OR 2 0, SO n R20 > S(0) n NR2 ⁇ R21> a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from
  • R9 and Rg a are independently hydrogen, C ⁇ -C(3 alkyl, substituted C ⁇ -C ⁇ alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m ⁇ O; or
  • R ⁇ and R ⁇ a taken together form a carbocyclic ring of 3-7 atoms or ;
  • R9 and R ⁇ o taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m ⁇ O; or
  • R9 and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms when m ⁇ O; or
  • R ⁇ and R2 taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
  • R ⁇ and A taken together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or
  • RXX and R ⁇ 2 are independently hydrogen , C ⁇ -C(3 alkyl, substituted C ⁇ -C6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms or a substituted carbocyclic ring containing 3-7 atoms; RXX and R ⁇ 2 taken together can form an optionally substituted ring of 3-7 atoms;
  • R ⁇ 3 is hydrogen, OH, NR7R8, NR ⁇ S ⁇ 2(C ⁇ -C6 alkyl),
  • R ⁇ 4 and R ⁇ 5 are independently hydrogen, C ⁇ -C ⁇ alkyl, substituted C ⁇ -C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN,
  • R20 and R21 are independently hydrogen , C -CQ alkyl, substituted C ⁇ -C6 alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ring containing 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, C ⁇ -C6-alkyl substituted by a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5;
  • R20 and R21 taken together can form an optionally substituted ring of 3-7 atoms;
  • X is N, O, S(0) n , C(O), (CR ⁇ R ⁇ 2)p, a single bond to Rs, C2-C6 alkenyl, substituted C2-C6 alkenyl,C2-C6 alkynyl, or substituted C2-C6 alkynyl; when X is O, S(0)n, C(O), or CR ⁇ R ⁇ 2 only Rg is possible;
  • m is 0-3; n is 0-2; p is 0-4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from C ⁇ -C ⁇ alkyl, C3-C7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C ⁇ -C6 alkoxy, fluoro, C(0)OR ⁇
  • R20 and R21 Preferred substituents when R20 and R21 are taken together include 7-aza-bicyclo[2.2.1]heptane and 2-aza-bicyclo[2.2.2] octane.
  • any variable e.g., aryl, heterocycle, R ⁇ ; etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
  • aryl includes phenyl and naphthyl. In a preferred embodiment, aryl is phenyl.
  • halogen or halo is intended to include fluorine, chlorine, bromine and iodine.
  • heterocycle or “heterocyclic ring” is defined by all non-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahy drop yri dine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • heterocyclic groups can exist in more than one tautomeric form. It is intended that all such tautomers be included within the ambit of this invention.
  • optical isomeric forms that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included.
  • These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof.
  • These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
  • the individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer.
  • the individual optical isomers may be prepared by asymmetric synthesis.
  • a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and other desirable properties.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts.
  • acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic, benzenesulfonic and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations.
  • pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl) aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl) aminome
  • esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • a preferred method for the synthesis of the substituted tryptamines described in this invention utilizes a palladium-catalyzed cross coupling reaction as a key step as shown in Scheme A.
  • This 6- azaindole synthesis involves the reaction of a suitably functionalized 3-amino-4-iodopyridine (1) with substituted acetylenes such as 2 in the presence of a base like sodium carbonate, lithium chloride, and a palladium catalyst such as (dppf)PdCl2 * CH2CI2.
  • the reaction is conducted in an inert organic solvent such as dimethylformamide at elevated temperatures, for instance at 100°C, and the reaction is conducted for a period of about 30 minutes to about 24 hours.
  • the acetylene utilized in this reaction may be a terminal acetylene (2a) or be optionally substituted on the terminal carbon atom with a substituent Z (2b, 2c).
  • the substituent abbreviated PGj. indicates an alcohol protecting group such as a benzyl ether, tert-butyl ether or the like.
  • the nature of the Z substituent determines the distribution of the 6-azaindole isomers (3 and 4) produced in the reaction.
  • the isomer 4a is the major product of the reaction.
  • the substituent Z is chosen to be a substituted silyl group such as trime hylsilyl, triethylsilyl (as shown), or the like, then isomer 3b is formed almost exclusively.
  • Z is a substituted aryl group, then both isomers 3c and 4c may be formed and the product mixture is separated using chromatographic or crystallization techniques to afford the individual isomers.
  • Scheme B illustrates the preparation of substituted 3- amino-4-iodopyridines (1) which are utilized in the 6-azaindole synthesis described in Scheme A.
  • Substituted 3-nitropyridine derivatives such as 5 are useful starting materials for the preparation of 3-amino-4- iodopyridines (1).
  • the 3-nitropyridines (5) bearing the desired substituents can in turn be prepared by the nitration of a pyridine derivative, by a nucleophilic aromatic substitution reaction from a suitable halogenated nitropyridine or by other methods known in the chemical literature.
  • the nitro substituent of a 3-nitropyridine is readily reduced to the required 3-amino group using a variety of methods such as catalytic hydrogenation and the resulting 3-amino group can then serve as a directing group for the subsequent introduction of an iodine at the 4 position of the pyridine.
  • the 3-amino group is first converted to a good ort ⁇ o-directing substituent such as a pivalamide (7). This is achieved by reacting the 3- aminopyridine 6 with pivaloyl chloride in the presence of an amine base like triethylamine in a suitable inert solvent followed by a standard workup and isolation.
  • the resulting pivalamide 7 is then subjected to ortbo-lithiation by treatment with a strong organolithium base such as tert-butyl lithium in the presence of a N,N,N',iV'-tetramethylethylene- diamine.
  • a strong organolithium base such as tert-butyl lithium
  • the ort io-lithiation is conducted in an inert solvent such as tetrahydrofuran at low temperature, typically -78°C, and the 4-lithiated derivative is the predominant regioisomer formed.
  • an iodinating reagent like iodine or iodine monochloride in a compatable solvent such as tetrahydrofuran and then allowed to warm to room temperature.
  • Acetylenic compounds of general structure 2 are prepared using one of several methods depending upon the choice of the desired substituents.
  • substituents R9, R ⁇ a, Rio and Rioa are selected to be hydrogen or lower alkyl groups
  • compounds of formula 2 may be prepared from known acetylenic alcohols such as 3-butyn-l-ol, 4-pentyn- 2-ol or similar acetylenic alcohols reported in the chemical literature.
  • the conversion of acetylenic alcohols of general formula 10 to acetylene derivatives of general formula 2 is shown in Scheme C.
  • the hydroxyl protecting group (PGi) illustrated in Scheme C is exemplified as an O-benzyl ether.
  • reaction of 10 with O-benzyl-2,2,2- trichloroacetimidate in the presence of a catalytic amount of a strong acid such as trifluoromethanesulfonic acid and in a suitable inert organic solvent like carbon tetrachloride at room temperature affords after 2 to 24 hours the protected acetylenic alcohol 2a.
  • Compounds of formula 2a may in turn be converted to acetylenes (2b) of general formula 2 wherein Z is a trialkylsilyl group by deprotonation of the acetylene with a base such as M-butyllithium in an inert organic solvent like tetrahydrofuran followed by reaction with a trialkylsilyl chloride such as trie thy lchlorosilane.
  • the deprotonation and silylation reactions are generally conducted at low temperatures, for instance between about -78 ° C and room temperature, and after standard workup and purification a silylacetylene of formula 2b is obtained.
  • acetylenes of general formula 2c wherein Z is an aryl or substituted aryl group are also useful in the 6- azaindole synthesis illustrated in Scheme A.
  • Arylacetylenes 2c may be prepared using a coupling reaction of cuprous acetylides derived from acetylenic alcohols of formula 2a with various aryl halides or aryl triflates (11). Such coupling reactions produce aryl acetylenes of general formula 12 as shown at the bottom of Scheme C.
  • acetylenic compounds of general formula 2a employs an ethynylation reaction sequence of aldehydes of general formula 16 as shown in Scheme D.
  • the aldehydes (16) used in the ethynylation sequence may be prepared using various methods known in organic synthesis starting with hydroxy- esters of general formula 13, from protected hydroxyesters of formula 14, or from alcohols related to the mono-hydroxyl protected diols of formula 15. The choice of preferred starting material depends upon the nature of the substituents R9, R ⁇ a, Rio, and R 10a selected. Scheme D illustrates this strategy begining with the generalized hydroxy ester 13.
  • the ester group of compounds of formula 14 can then be converted to an aldehyde of formula 16 either directly using a reagent like diisobutylaluminum hydride in a solvent like toluene, or through a two step process.
  • a reagent such as lithium aluminum hydride in tetrahydrofuran
  • alcohols of formula 15 which are then subjected to reoxidation, for instance using a Swern-Moffatt oxidation, to afford the desired aldehydes of formula 16.
  • aldehydes of formula 16 are reacted with carbon tetrabromide and triphenylphosphine in an inert organic solvent like dichloromethane to produce the dibromo olefins of formula 17.
  • the dibromo olefins (17) are treated with two equivalents of a strong base such as n-butyllithium in tetrahydrofuran at low temperature, for instance at about -78°C.
  • the strong base induces dehydrohalogenation and metal- halogen exchange to afford lithium acetylides which upon quenching and workup afford acetylenes of general formula 2a.
  • the intermediate lithium acetylides formed in the reaction may be treated with a trialkylsilyl chloride, such as triethylchlorosilane, to afford silylacetylenes of general formula 2b.
  • the conversion of 2-silyl-substituted 6-azaindoles of general formula 3b to 2-aryl-substituted 6-azaindoles of general formula 3c may be accomplished in two steps as shown in Scheme E.
  • the first step is a halodesilylation reaction which converts silyl-substituted 6-azaindoles of formula 3b into 2-halo-6-azaindoles of general formula 18.
  • Scheme E illustrates this process using iodine monochloride so that the product obtained is a 2-iodoindole of general formula 18.
  • Silver tetrafluoroborate is also employed in this example to increase the reactivity of the halogenating reagent.
  • the second step is a palladium-catalyzed cross coupling reaction of the 2-halo-6-azaindole 18 with a suitable aryl or substituted aryl organometallic reagent 19.
  • Scheme E illustrates this process with an aryl or substituted arylboronic acid as the organometallic reagent, however, other organometallic reagents known to participate in palladium-catalyzed cross-coupling reactions such as arylboronic esters or arylstannanes may also be employed.
  • a 2-iodo-6- azaindole of general formula 18 is coupled with a generalized boronic acid (19) using a catalyst such as [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (shown), tetrakis (triphenylphosphine)-palladium(O) or the like.
  • a catalyst such as [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (shown), tetrakis (triphenylphosphine)-palladium(O) or the like.
  • the reaction is usually conducted at temperatures between room temperature and about 100°C, for instance at about 80°C.
  • This palladium catalyzed cross-coupling reaction may be effected using various combinations of palladium catalysts and solvent compositions known in organic chemistry, and the selection of the conditions is made depending upon the type of organometallic reagent (19) used and the identity of the substituent groups in the two starting materials.
  • organometallic reagent is a boronic acid or boronate ester
  • a preferred solvent mixture consists of toluene, ethanol and an aqueous solution of a base like cesium or sodium carbonate.
  • the organometallic reagent 19 is an arylstannane, then no additional base is required, and a polar aprotic solvent such as tetrahydrofuran or dimethylformamide is employed.
  • an appropriate amine protecting group (PG2) for the 6-azaindole is determined primarily by which protecting group (PGi) is present on the hydroxyl group in the C-3 sidechain, and by consideration of the chemical stability of the amine protecting group (PG required in the remaining steps of the synthesis.
  • the hydroxyl protecting group (PGi) is anO-benzyl ether as illustrated previously in Schemes C and D
  • the 6-azaindole may be protected as a carbamate derivative such as a tert-butylcarbamate (BOC).
  • the BOC-protected 6-azaindole is stable under the hydrogenolysis conditions which are used to remove the O-benzyl ether and it may be conveniently removed at the end of the synthesis using acidic conditions. If it is desired to synthesize compounds of formula (I) wherein Ro is alkyl, substituted alkyl or the like, then it is possible to introduce that substituent at this point and the use of a protecting group and its subsequent removal is not required.
  • An alcohol of general formula 21 may be converted to a primary amine of general formula 23 using a variety of methods known in the literature of organic chemistry.
  • the bottom of Scheme F illustrates a process where the alcohol 21 is first converted to an azide of general formula 22, followed by reduction to afford the amine derivative 23.
  • the synthesis of an azide of general formula 22 from alcohols like 21 is best accomplished by performing a Mitsunobu reaction in the presence of an appropriate azide source such as diphenylphosphoryl azide or zinc azide pyridine complex.
  • Scheme F illustrates the reaction of alcohol 21 with triphenylphosphine, diethylazodicarboxylate, zinc azide pyridine complex and a proton source such as imidazole in an inert solvent like methylene chloride or tetrahydrofuran.
  • the reaction is usually conducted at room temperature for periods between 1-24 hours, typically overnight or about 15 hours, and affords the azide of general formula 22 in good yield.
  • an azide of formula 22 may then be reduced to an amine of formula 23 using one of several methods common in organic synthesis.
  • One preferred method is catalytic hydrogenation in a solvent like methanol or ethanol in the presence of a catalyst such as 10% palladium on carbon.
  • azides like 22 may be reacted with triphenylphosphine to form an iminophosphorane which upon hydrolysis with water affords the amine of formula 23 and triphenylphophine oxide.
  • the final stage of the synthesis of the novel 6-azaindole derivatives (I) involves elaboration of the sidechain at the C-3 position of the 6-azaindole core.
  • One method for the completion of the synthesis is illustrated in Scheme G.
  • the 2-aryltryptamine (23) may be condensed with a carboxylic acid of type 24 using the coupling reagent l-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexyl-carbodiimide (DCC) or the like with or without 1- hydroxybenzotriazole (HOBt) and a tertiary amine base such as N- methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours to provide the corresponding amide derivative (
  • 2- aryltryptamine 23 can be treated with an active ester or acid chloride of formula 26 in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0°-25°C for 30 minutes to 4 hours to give compound 25.
  • an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like
  • a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like
  • the amide carbonyl of 25 can be reduced by treatment with borane, lithium aluminum hydride, or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at about 25°C to about 100°C, preferably about 65°C, for a period of 1-8 hours to give the corresponding amine 27.
  • borane, lithium aluminum hydride, or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at about 25°C to about 100°C, preferably about 65°C, for a period of 1-8 hours to give the corresponding amine 27.
  • the 2-aryltryptamine 23 can be modified by treatment with an aldehyde or ketone of type 28 in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like, with or without a dessicant such as 3A molecular sieves or magnesium sulfate, and a hydride source such as sodium borohydride or sodium cyanoborohydride, in an inert organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, or mixtures thereof at a temperature of about 0° to about 25°C for a period of 1-12 hours to give the corresponding secondary or tertiary amine derivative 29.
  • a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like
  • a dessicant such as 3A molecular sieves or magnesium sulfate
  • a hydride source such as sodium
  • the tryptamine 23 can be modified using the Fukuyama modification of the Mitsunobu reaction (Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373- 74).
  • the tryptamine 23 may be reacted with an arylsufonyl chloride such as 2-nitrobenzene-sulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzene-sulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent such as methylene chloride to provide the corresponding sulfonamide 30.
  • an arylsufonyl chloride such as 2-nitrobenzene-sulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzene-sulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like
  • an inert organic solvent such as methylene chloride
  • the sulfonamides can be further modified by reaction with an alcohol of type 31 in the presence of triphenylphosphine and an activating agent such as diethylazodicarboxylate (DEAD), diisopropylazodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfonamide adduct.
  • DEAD diethylazodicarboxylate
  • diisopropylazodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfonamide adduct.
  • DEAD diethylazodicarboxylate
  • diisopropylazodicaboxylate diisopropylazodicaboxylate or the like
  • an inert organic solvent such as benzene, toluene
  • a mono-nitrobenzenesulfonyl derivative When a mono-nitrobenzenesulfonyl derivative is employed, the removal of the sulfonamide is accomplished with a more nucleophilic reagent such as thiophenol or mercaptoacetic acid in combination with lithium hydroxide in DMF.
  • a more nucleophilic reagent such as thiophenol or mercaptoacetic acid in combination with lithium hydroxide in DMF.
  • Reaction Scheme K illustrates a method that is complimentary to reaction Scheme J for completing the synthesis of the novel compounds of formula (I).
  • Scheme K also employs the Fukuyama modification of the Mitsunobu reaction similar to that illustrated in reaction Scheme J.
  • the alcohol partner employed is a 2-aryltryptophol of general formula 21 which has been decribed previously in reaction Scheme F.
  • the 2-aryltryptophol (21) is reacted with a substituted sulfonamide of general formula 33, triphenylphosphine and diethylazodicarboxylate in a suitable inert organic solvent such as benzene, tetrahydrofuran, 1,4-dioxane or the like.
  • the reaction is generally conducted at room temperature for a period of 2 to 24 hours, typically overnight or for about 12-16 hours.
  • the product is an N,N-disubstituted sulfonamide which is then separately subjected to reaction with a base such as / ⁇ -propylamine which removes the sulfonamide substituent and furnishes a secondary amine related to formula 32.
  • the sulfonamides of formula 33 employed are readily obtained from a primary amine and either 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonyl chloride (as shown) in the presence of a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent such as methylene chloride.
  • PG2 6-azaindole nitrogen atom
  • Rat pituitary GnRH receptor binding assay Crude plasma membranes prepared from rat pituitary tissues were incubated in a Tris.HCl buffer (50 mM, PH. 7.5) containing bovine serum albumin (.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and the desired concentration of a test compound. The assay mixtures were incubated at 4°C for 90-120 minutes followed by rapid filtration and repeated washings through a glass fiber filter. The radioactivity of membrane bound radioligands was determined in a gamma-counter. From this data, the IC50 of the radioligand binding to GnRH receptors in the presence of test compound was estimated.
  • the compounds to be assayed were dissolved and diluted in DMSO.
  • the final concentration of DMSO in the incubation medium was 0.5%.
  • the Wistar male rats (150-200 grams) were obtained from Charles River Laboratories (Wilmington, MA). Rats were maintained at a constant temperature (25°C) on a 12-hr light, 12-hr dark cycle. Rat chow and water were available ad libitum. The animals were sacrificed by decapitation and pituitary glands were aseptically removed and placed in Hank's Balanced Salt Solution (HBSS) in a 50-mL polypropylene centrifuge tube. The collection tube was centrifuged for 5 min at 250 x g, and HBSS was removed by aspiration. Pituitary glands were transferred to a disposable petri plate and minced with a scalpel.
  • HBSS Hank's Balanced Salt Solution
  • the minced tissue was then transferred to a 50-mL disposable centrifuge tube by suspending the tissue fragments in three successive 10-mL aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase.
  • the cell dispersion was carried out in a water bath at 37°C with gentle stirring for 30 min.
  • the cells were aspirated 20 to 30 times with a pipet and the undigested pituitary fragments were allowed to settle for 3 to 5 min.
  • the suspended cells were removed by aspiration, and then subjected to a 1200 x g centrifugation for 5 min. The cells were then resuspended in Culture medium.
  • the undigested pituitary fragments were treated with 30 mL aliquots of the digestion enzymes as above for a total of 3 digestions with the collagenase/hyaluronidase mixture.
  • the resulting cell suspensions were pooled, counted and diluted to a concentration of 3 x 10 ⁇ cells/ml, and 1.0 ml of this suspension was placed in each well of a 24-well tray (Costar, Cambridge, MA). Cells were maintained in a humidified 5% C ⁇ 2-95% air atmosphere at 37°C for 3 to 4 days.
  • the culture medium consisted of DMEM containing 0.37% NaHC ⁇ 3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% glutamine, and 0.1% gentamycin.
  • DMEM containing 0.37% NaHC ⁇ 3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids(lOOX), 1% glutamine (100X), 1% Penicillin/Streptomycin (10,000 Units of Penicillin and 10,000 micrograms of Streptomycin per ml), and 25 mM HEPES, pH 7.4.
  • LH release was initiated by adding 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicate. Incubation was carried out at 37°C for 3 hr. After incubation, medium was removed and centrifuged at 2,000 x g for 15 min to remove any cellular material. The supernatant fluid was removed and assayed for LH content with a double antibody RIA procedure using materials obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center, Torrance, CA).
  • the compounds of formula I are useful in a number of areas affected by GnRH. They may be useful in sex-hormone related conditions, sex-hormone dependent cancers, benign prostatic hypertrophy or myoma of the uterus. Sex-hormone dependent cancers which may benefit from the administration of the compounds of this invention include prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. Other sex-hormone dependent conditions which may benefit from the administration of the compounds of this invention include endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty.
  • the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril
  • an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • the compounds of the invention may also be useful for controlling pregnancy, as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and for the treatment of sleep disorders such as sleep apnea.
  • a further use of the compounds of this invention is as an adjunct to growth hormone therapy in growth hormone deficient children.
  • the compounds may be administered with growth hormone or a compound which increases the endogenous production or release of growth hormone.
  • Certain compounds have been developed which stimulate the release of endogenous growth hormone.
  • Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J.
  • WO 95/13069 PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; Science. 260. 1640-1643 (June 11, 1993); Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).
  • Representative preferred growth hormone secretagoues employed in the present combination include the following:
  • the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful for the treatment of bone lithiasis as disclosed in U.S. Patent 4,621,077 to Rosini, et al.
  • the literature discloses a variety of bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S. Patent No. 3,584,125; U.S. Patent No. 3,940,436; U.S. Patent No. 3,944,599; U.S. Patent No. 3,962,432; U.S. Patent No. 4,054,598; U.S. Patent No. 4,267,108; U.S. Patent No. 4,327,039; U.S. Patent No. 4,407,761; U.S. Patent No. 4,578,376; U.S. Patent No.
  • bisphosphonic acids and halo- bisphosphonic acids are well known in the art. Representative examples may be found in the above mentioned references which disclose the compounds as being useful for the treatment of disturbances of calcium or phosphate metabolism, in particular, as inhibitors of bone resorption.
  • Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-l-hydroxy- hexylidene-bisphosphonic acid, and l-hydroxy-3(methylpentyl- amino)-propylidene-bisphosphonic acid;or any pharmaceutically acceptable salt thereof.
  • a particularly preferred bisphosphonate is alendronic acid (alendronate), or a pharmaceutically acceptable salt thereof.
  • An especially preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received regulatory approval for marketing in the United States under the trademark FOSAMAX®.
  • a compound of the present invention may be co-administered with a 5 ⁇ -reductase 2 inhibitor, such as finasteride or epristeride; a 5 ⁇ -reductase 1 inhibitor such as 4,7 ⁇ -dimethyl-4-aza- 5 -cholestan-3-one, 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(4-chlorophenoxy)- 5 ⁇ -androstane, and 3-oxo-4-aza-4,7 ⁇ -dimethyl-16 ⁇ -(phenoxy)-5 ⁇ - androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5 ⁇ -reductase 1 and 5 ⁇ -reductase 2 such as 3-oxo-4-aza- 17 ⁇ -(2,5-trifluoromethylphenyl-carbamoyl)-5 ⁇ -androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • the active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutic- ally elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxy methylcellulose , methylcellulose , hy droxypropylmethyl-cellulose , sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphat
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of, these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the following examples illustrate the preparation of some of the compounds of the invention and are not to be construed as limiting the invention disclosed herein.
  • Step 1A (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2- ⁇ 2-(3,5-dimethylphenyl)- 3-[2-[N-(2,4-dinitrobenzenesulfonyl),N-(4-carbomethoxy- phenyl)amino]-l-methylethyl]-lH-(tert-butoxycarbonyl)-
  • reaction mixture was concentrated in vacuo and the residue was partially purified by flash chromatography on silica gel (40-50% ethyl acetate/hexanes as eluent) to give a mixture of the title compound, 1,2-dicarbethoxyhydrazine and triphenylphosphine oxide.
  • Step IB (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2- ⁇ 2-(3,5-dimethylphenyl)- 3- ⁇ l-methyl-2-[(4-carbomethoxyphenyl)ethylamino]ethyl ⁇ -lH- (tert-butoxycarbonyl)pyrrolo[2,3-c]pyridin-5-yl ⁇ -2-methyl- propan-1-one
  • Step 1C (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2- ⁇ 2-(3,5-dimethylphenyl)- 3- ⁇ l-methyl-2-[(4-carbomethoxyphenyl)ethylamino]ethyl ⁇ -l pyrrolo[2,3-c]pyridin-5-yl ⁇ -2-methylpropan-l-one
  • Step 2A (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2- ⁇ 2-(3,5-dimethylphenyl)- 3- ⁇ l-methyl-2-[(4-carboxyphenyl)ethylamino]ethyl ⁇ -lH- pyrrolo-[2,3-c]-pyridin-5-yl ⁇ -2-methylpropan-l-one trifluoroacetic acid salt
  • Step B (-S f )-3-Benzyloxy-2-methylpropan-l-ol
  • An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a reflux condenser and a 500 mL constant pressure addition funnel. The flask was charged with a solution of 62.252 g (0.299 mol) of methyl (S)-3-benzyloxy-2- methylpropanoate in 600 mL of anhydrous THF, and a 1.0 M solution of lithium aluminum hydride (300 mL; 0.3 mol) was transferred into the dropping funnel via a cannula.
  • Step D dS)-4-Benzyloxy-l,l-dibromo-3-methylbutene
  • An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a thermometer, an N2 inlet, and a septum.
  • the flask was charged with 180.71 g (0.689 mol) of triphenylphosphine and 925 mL of CH2CI2.
  • the reaction mixture w ⁇ as stirred under an N 2 atmosphere and cooled to 0-5°C with an external ice-water bath.
  • the stirrer was started and the crude reaction mixture was introduced as a slow stream which resulted in formation of a granular precipitate. After the transfer was complete the reaction mixture was filtered and the solids were carefully washed with hexane. The filtrate was evaporated in vacuo and additional solids were deposited. The residue was resuspended in hexane, filtered and the filtrate reevaporated. The resulting oil was purified by Kugelrohr distillation to afford 46.54 g (81% for two steps) of the title compound as an oil.
  • Step E (-S)-(4-benzyloxy-3-methylbut-l-vnyl)triethylsilane
  • An oven dried 100 mL single-necked round bottom flask was equipped with a magnetic stir bar and a septum then charged with 5.171 g (15.5 mmol) of (-S)-4-benzyloxy-l,l-dibromo-3-methylb tene and 20 mL of anhydrous THF.
  • the reaction mixture was stirred at -78°C under an N2 atmosphere and 12.4 mL of a 2.5 M solution of / -butyllithium (31.0 mmol) was added dropwise via syringe over 15 min.
  • Step AA t ⁇ rt-Butyl methyl 2-(5-nitropyridin-2-yl)malonate
  • Step BB Methyl (5-nitropyridin-2-yl)acetate
  • Trifluoroacetic acid (34.2 mL, 0.444 mol.) was added, via syringe, to a stirred solution of crude tert-butyl methyl 2-(5-nitropyridin- 2-yl)malonate (0.148 mol.) in dichloromethane (500 mL) at ambient temperature. After approximately 2h, the reaction mixture was poured cautiously onto cold saturated aqueous NaHC0 3 and extracted with ethyl acetate ( ⁇ 3). The combined organic extract was washed with brine, dried (MgS0 ) and concentrated in vacuo.
  • Step CC Methyl 2-methyl-2-(5-nitropyridin-2-yl)propionate
  • Step DD Methyl 2-(5-aminopyridin-2-yl)-2-methylpropionate
  • a mixture of methyl 2-methyl-2-(5-nitropyridin-2-yl) propionate (17.5 g, 78.0 mmol.) and and Pd/C (Pd-10%; 600 mg) in methanol (150 mL) was hydrogenated at 50 psi for 0.75h. An exothermic reaction was observed! The resulting mixture was filtered through celite ® washing copiously with methanol and the filtrate evaporated in vacuo . The residual oil was sufficiently pure to be used without further purification in the subsequent reaction.
  • Step EE Methyl 2-[5-(2,2-dimethylpropionylamino)pyridin-2-yl]-2- methylpropionate
  • Trimethylacetyl chloride (11.5 mL, 93.6 mmol.) was added dropwise, via syringe, to a stirred solution of crude methyl 2-(5- aminopyridin-2-yl)-2-methylpropionate (78.0 mmol.) and triethylamine (13.0 mL, 93.6 mmol.) in a mixture of diethyl ether/THF (1:1; 600 mL) at 0°C. After approximately 0.5h, the reaction mixture was warmed to room temperature, poured into water and extracted with ethyl acetate (x3). The combined organic extract was washed with water, brine, dried (MgS0 ) and concentrated in vacuo. The residual oil was sufficiently pure to be used without further purification in the subsequent reaction.
  • Step FF 2-[5-(2,2-Dimethylpropionylamino)pyridin-2-yl]-2-methyl- propionic acid
  • Step GG N- ⁇ 6-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-l,l-dimethyl-2-oxoethyl]- pyridin-3-yl ⁇ -2,2-dimethylpropionamide
  • Step HH iV- ⁇ 6-[2-(2-Azabicyclo[2.2.2]oct-2-yl)-l,l-dimethyl-2-oxoethyl]- 4-iodopyridm-3-yl ⁇ -2,2-dimethylpropionamide
  • Step JJ (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2-[3-(2-benzyloxy-l-methyl- ethyl)-2-triethylsilyl-lH-pyrrolo[2,3-c]pyridin-5-yl]-2- methylpropan-1-one
  • the reaction mixture was diluted with ethyl acetate and filtered through celite ® washing copiously with ethyl acetate.
  • the filtrate was poured into water/brine (1:1) and the organic phase separated.
  • the aqueous phase was re-extracted with ethyl acetate ( ⁇ 2), the combined organic extract washed with brine, dried (MgS0 ) and concentrated in vacuo.
  • the residue was purified by flash chromatography on silica gel (gradient elution; 70-80% ethyl acetate/hexanes as eluent) to give the title compound as a foam (2.59 g, 62%).
  • Step KK (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2-[3-(2-benzyloxy-l-methyl- ethyl)-2-iodo-lH-pyrrolo[2,3-c]pyridin-5-yl]-2-methyl propan-1-one IPy2BF 4 (2.51 g, 6.75 mmol.) was added in one portion to a stirred solution of (S)-l-(2-azabicyclo[2.2.2]oct-2-yl)-2-[3-(2-benzyloxy- l-methyl-ethyl)-2-triethylsilyl-lH-pyrrolo[2,3-c]pyridin-5-yl]-2- methylpropan-1-one (2.52 g, 4.50 mmol.) in dichloromethane (45 mL) at room temperature.
  • Trifluoromethanesulfonic acid (1.19 mL, 13.5 mmol.) was then added over approximately 3min, via syringe, and the resulting mixture stirred at ambient temperature for 1.5h.
  • the reaction mixture was poured into cold saturated aqueous NaHC0 3 /lM Na2S2 ⁇ 3 (1:1) and extracted with ethyl acetate ( ⁇ 3).
  • the combined organic extract was washed with water, brine, dried (MgS0 ) and concentrated in vacuo.
  • Step LL (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2-[3-(2-benzyloxy-l-methyl- ethyl)-2-(3,5-dimethylphenyl)-lH-pyrrolo[2,3-c]pyridin-5-yl]-
  • Step MM (_5)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2- ⁇ 3-(2-benzyloxy-l- methylethyl)-2-(3,5-dimethylphenyl)-lH-(tert-butoxy- carbonyl)pyrrolo[2.3-c1pyridin-5-yl)-2-methylpropan-l-one Di-t-eri-butyl-dicarbonate (1.43 g, 4.37 mmol) was added to stirred suspension of ( ⁇ S)-l-(2-azabicyclo[2.2.2]oct-2-yl)-2-[3-(2-benzyloxy- l-methyl-ethyl)-2-(3,5-di
  • Step NN (S)-l-[2-(2-Azabicyclo[2.2.2]oct-2-yl)]-2- ⁇ 2-(3,5-dimethyl- phenyl)-3-(2-hydroxy-l-methylethyl)-lH-(tert-butoxy- carbonyl)pyrrolo[2,3-c]pyridin-5-vi
  • Step PP (S)-2- ⁇ 3-(2-Amino-l-methylethyl)-2-(3,5-dimethylphenyl)-lH- (tert-butoxycarbonyl)pyrrolo[2,3-c]pyridin-5-yl ⁇ -l-(2-aza- bicyclo[2.2.21oct-2-yl)-2-methylpropan- 1-one
  • Step QQ (S)-l-(2-Azabicyclo[2.2.2]oct-2-yl)-2- ⁇ 2-(3,5-dimethylphenyl)- 3-[2-(2,4-dinitrobenzenesulfonylamino)-l-methylethyl]-lH- (tert-butoxycarbonyl)pyrrolo[2,3-c]pyridin-5-yl ⁇ -2-methyl- propan- 1-one

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Abstract

L'invention porte sur des composés de formule (I) et leurs sels pharmacocompatibles utiles comme antagonistes de la GnRH, et de ce fait pour le traitement de différents états liés aux hormones sexuelles, et autres états, chez l'homme et chez la femme.
PCT/US2000/005727 1999-03-10 2000-03-06 Composes de 6-azaindole antagonistes de la gonadoliberine WO2000053180A1 (fr)

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EP00912179A EP1165075A4 (fr) 1999-03-10 2000-03-06 Composes de 6-azaindole antagonistes de la gonadoliberine
JP2000603669A JP2002538205A (ja) 1999-03-10 2000-03-06 性腺刺激ホルモン放出ホルモン拮抗薬としての６−アザインドール化合物
AU33950/00A AU3395000A (en) 1999-03-10 2000-03-06 6-azaindole compounds as antagonists of gonadotropin releasing hormone
CA002367121A CA2367121A1 (fr) 1999-03-10 2000-03-06 Composes de 6-azaindole antagonistes de la gonadoliberine

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US6809098B2 (en) 2001-02-20 2004-10-26 Astrazeneca Ab Compounds
US7132442B2 (en) 2002-08-21 2006-11-07 Astrazeneca Ab 6H-thieno[2, 3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7253290B2 (en) 2002-08-21 2007-08-07 Astrazeneca Ab Pyrazole derivatives as GnRH inhibitors
US7256188B2 (en) 2001-05-14 2007-08-14 Astrazeneca Ab 3-aminoalkyl-2-aryl-indole derivatives and their use as GnRH antagonists
US7306922B2 (en) 2000-09-15 2007-12-11 Astrazeneca Ab Human and rat PGC-3, PPAR-gamma coactivations and splice variants thereof
US7317010B2 (en) 2002-08-21 2008-01-08 Astrazeneca Ab Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone
US7449489B2 (en) 2002-08-21 2008-11-11 Astrazeneca Ab Indolylalkylamino-methylidenecarbamate derivatives useful as GnRH antagonists
US7514570B2 (en) 2002-08-21 2009-04-07 Astrazeneca Ab Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (GnRH) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer
US7589206B2 (en) 2004-06-09 2009-09-15 Glaxo Group Limited Pyrrolopyridine derivatives
WO2020037001A1 (fr) * 2018-08-14 2020-02-20 Osteoqc Inc. COMPOSÉS β-CARBOLINE FLUORÉS
US10947236B2 (en) 2018-08-14 2021-03-16 Osteoqc Inc. Pyrrolo-dipyridine compounds
US11267814B2 (en) 2013-03-14 2022-03-08 OsteoQC, Inc. Compounds for bone growth

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US20120004182A1 (en) * 2010-07-02 2012-01-05 Carsten Gruendker Pharmaceutical compositions and methods for induction and enhancement of apoptosis in tumor cells
WO2018002673A1 (fr) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Nouvelles formulations d'antagonistes du récepteur de l'angiotensine ii

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7306922B2 (en) 2000-09-15 2007-12-11 Astrazeneca Ab Human and rat PGC-3, PPAR-gamma coactivations and splice variants thereof
US6809098B2 (en) 2001-02-20 2004-10-26 Astrazeneca Ab Compounds
US7256188B2 (en) 2001-05-14 2007-08-14 Astrazeneca Ab 3-aminoalkyl-2-aryl-indole derivatives and their use as GnRH antagonists
US7514570B2 (en) 2002-08-21 2009-04-07 Astrazeneca Ab Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (GnRH) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer
US7268158B2 (en) 2002-08-21 2007-09-11 Astrazeneca Ab 6H-THIENO [2,3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7253290B2 (en) 2002-08-21 2007-08-07 Astrazeneca Ab Pyrazole derivatives as GnRH inhibitors
US7317010B2 (en) 2002-08-21 2008-01-08 Astrazeneca Ab Thieno-pyrrole compounds as antagonists of gonadotropin releasing hormone
US7449489B2 (en) 2002-08-21 2008-11-11 Astrazeneca Ab Indolylalkylamino-methylidenecarbamate derivatives useful as GnRH antagonists
US7132442B2 (en) 2002-08-21 2006-11-07 Astrazeneca Ab 6H-thieno[2, 3-b]pyrrole derivatives as antagonists of gonadotropin releasing hormone (GnRH)
US7547722B2 (en) 2002-08-21 2009-06-16 Astrazeneca Ab Chemical compounds
US7589206B2 (en) 2004-06-09 2009-09-15 Glaxo Group Limited Pyrrolopyridine derivatives
US11267814B2 (en) 2013-03-14 2022-03-08 OsteoQC, Inc. Compounds for bone growth
WO2020037001A1 (fr) * 2018-08-14 2020-02-20 Osteoqc Inc. COMPOSÉS β-CARBOLINE FLUORÉS
US10947236B2 (en) 2018-08-14 2021-03-16 Osteoqc Inc. Pyrrolo-dipyridine compounds
US11655250B2 (en) 2018-08-14 2023-05-23 Osteoqc Inc. Pyrrolo-dipyridine compounds
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JP2002538205A (ja) 2002-11-12
EP1165075A1 (fr) 2002-01-02
AU3395000A (en) 2000-09-28

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